The management of pain remains a major medical problem that is due, at least in part, to an incomplete understanding of the physiologic mechanisms for transduction of noxious stimuli. Both pharmacological and gene deletion studies have demonstrated a pivotal role for TRPV1 (transient receptor potential subtype V1) in inflammatory heat hyperalgesia and thermoregulation and this receptor is expressed in a significant proportion of pain-sensing sensory neurons, termed nociceptors. Interestingly, the precise mechanism(s) for the endogenous activation of TRPV1 remains unknown. In this application, we will evaluate the innovative hypothesis that TRPV1 activities are regulated by endogenous oxidized linoleic acid metabolites (OLAMs). Our preliminary data demonstrate that heat evokes the release of linoleic acid metabolites that comprise a new family of physiologically relevant TRPV1 agonists by contributing to the heat responsiveness of this channel. Based upon previous studies and our own results, we propose the central hypothesis that certain peripheral stimuli trigger the release of OLAMs that regulate TRPV1 activities. Specific Aim 1: Determine the key enzymatic pathway(s) involved in the generation of OLAM- induced TRPV1 activation in cultured sensory neurons. Specific Aim 2: Evaluate the physiologic relevance of key peripheral enzymatic pathway(s) regulating OLAM-induced TRPV1 activities in control vs inflamed skin biopsies. Specific Aim 3: Evaluate the physiologic relevance of key peripheral enzymatic pathway(s) for regulating inflammatory thermal hyperalgesia/allodynia in vivo. This novel hypothesis may have considerable medical significance since mechanisms inhibiting OLAM synthesis or function may comprise novel targets for analgesic drug development. In addition, the discovery of OLAM regulation of TRPV1 activities provides a novel and previously unknown mechanism for pain transduction that may promote fundamental research into cellular transduction of noxious stimuli as well as research on preclinical pain models ranging from inflammation to neuropathic conditions to cancer-related pain.